Dynamic Trajectories of Pupillary Light Reflex Parameters and Prognosis in Critically Ill Patients: A Multicenter Prospective Cohort Study (PUPIL)

This multicenter prospective observational cohort study aims to investigate the association between early dynamic trajectories of pupillary light reflex parameters and clinical outcomes in critically ill patients admitted to emergency intensive care units. Quantitative pupillometry will be performed during the first 7 days after EICU admission. Constriction velocity will be the primary parameter for trajectory analysis, while dilation velocity, pupil diameter, constriction percentage, maximum constriction velocity, and latency will be analyzed as supplementary parameters. The study will evaluate whether these dynamic pupillary trajectories are associated with discharge outcome and 90-day functional outcome assessed by the Glasgow Outcome Scale-Extended.

Study Overview

• Status: Not yet recruiting
• Conditions: Critical Illness; Prognosis; Pupillometry

Detailed Description

Critically ill patients admitted to emergency intensive care units often have complex underlying conditions, rapid changes in disease severity, fluctuating organ function, and multiple therapeutic influences. Conventional assessment tools, including vital signs, Glasgow Coma Scale, RASS, CPOT, APACHE II, laboratory tests, and imaging examinations, are important in clinical practice but may be limited by subjectivity, intermittent availability, or reduced reliability in patients receiving sedation, analgesia, mechanical ventilation, or organ support.

The pupillary light reflex is a classic component of neurological examination. Automated quantitative pupillometry provides objective and reproducible measurements of pupillary light reflex parameters, including pupil diameter, constriction velocity, dilation velocity, constriction percentage, maximum constriction velocity, and latency. These parameters may reflect brainstem reflex function, autonomic nervous system activity, medication effects, pain, circulatory status, and systemic stress responses in critically ill patients.

This study will enroll adult critically ill patients admitted to participating emergency intensive care units. After written informed consent is obtained from the participant or a legally authorized representative, baseline demographic data, primary diagnosis, disease severity scores, treatment information, organ support, sedation and analgesia status, vasoactive medication use, and vital signs will be collected. Pupillary light reflex parameters will be measured using a handheld automated quantitative pupillometer once daily during the first 7 days after EICU admission, or until EICU discharge or death, whichever occurs first. Additional measurements may be performed when clinically indicated.

The primary analysis will focus on the dynamic trajectory of constriction velocity during the early EICU period. Dilation velocity, pupil diameter, constriction percentage, maximum constriction velocity, and latency will be analyzed as supplementary pupillary light reflex parameters. Group-based trajectory modeling will be used to identify distinct longitudinal trajectory patterns of pupillary light reflex parameters.

The primary outcome is 90-day functional outcome assessed by the Glasgow Outcome Scale-Extended. Unfavorable functional outcome is defined as a GOS-E score of 4 or lower, and death during follow-up will be included in the GOS-E scoring system. The secondary outcome is discharge outcome, which will be analyzed primarily as a binary outcome. Favorable discharge outcome is defined as discharge home or transfer to a rehabilitation facility. Unfavorable discharge outcome is defined as in-hospital death, discharge to hospice or long-term care facility, or discharge against medical advice. Transfer to a higher-level hospital or another medical institution for continued treatment will be recorded as an indeterminate disposition and further followed when feasible.

This study will further evaluate whether dynamic trajectories of pupillary light reflex parameters provide additional prognostic value beyond conventional static measurements and clinical variables. No treatment assignment or intervention will be performed as part of this study. All clinical management decisions will be made by the treating physicians according to routine clinical practice.

• Study Type: Observational
• Enrollment (Estimated): 700

Contacts and Locations

• Study Contact: Name: Danni Jin, MD; Phone Number: +8615825512455; Email: 670251925@qq.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult critically ill patients admitted to emergency intensive care units at participating tertiary hospitals will be screened for eligibility. Eligible patients are those expected to stay in the EICU for more than 48 hours and for whom reliable quantitative pupillometry can be performed. Written informed consent will be obtained from the participant or a legally authorized representative before enrollment.

Description

Inclusion Criteria:

1. Age 18 years or older.
2. Admission to the emergency intensive care unit.
3. Critically ill patients with an expected EICU stay longer than 48 hours.
4. Written informed consent obtained from the participant or legally authorized representative.

Exclusion Criteria:

1. Severe ocular disease, severe ocular trauma, postoperative ocular status, or other conditions that prevent reliable pupillary measurement.
2. Known neuro-ophthalmic disorders that may affect the pupillary light reflex, such as oculomotor nerve palsy.
3. Use of topical ophthalmic medications during the study period that may significantly affect pupillary response, when their effects cannot be accurately recorded or evaluated.
4. Pregnancy or breastfeeding.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Adult critically ill patients admitted to the EICU; Adult critically ill patients admitted to emergency intensive care units who meet the eligibility criteria will be enrolled in a single prospective observational cohort. Participants will undergo quantitative pupillometry during the first 7 days after EICU admission, or until EICU discharge or death, whichever occurs first. Clinical information, treatment data, discharge outcome, and 90-day functional outcome will be collected.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
90-Day Functional Outcome Assessed by the Glasgow Outcome Scale-Extended	Functional outcome will be assessed using the Glasgow Outcome Scale-Extended at 90 days after disease onset. Unfavorable functional outcome is defined as a GOS-E score of 4 or lower. Participants who die during follow-up will be included in the GOS-E scoring system, and the 90-day mortality rate will be reported separately.	90 days after disease onset

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Discharge Outcome	Discharge outcome will be analyzed primarily as a binary outcome: favorable versus unfavorable discharge outcome. Favorable discharge outcome is defined as discharge home or transfer to a rehabilitation facility. Unfavorable discharge outcome is defined as in-hospital death, discharge to hospice, transfer to a long-term care facility, or discharge against medical advice. Transfer to a higher-level hospital or another medical institution for continued treatment will be recorded as an indeterminate disposition and further followed when feasible.	From EICU admission to hospital discharge; indeterminate transfers will be followed up to 90 days when feasible

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
• Collaborators: First People's Hospital of Hangzhou; Ningbo Medical Center Lihuili Hospital; Zhejiang Provincial People's Hospital; Jinhua Municipal Central Hospital; Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University; The Second Affiliated Hospital of Jiaxing University; People's Hospital of Quzhou; Lishui Country People's Hospital; Zhejiang Provincial Tongde Hospital; The Fourth Affiliated Hospital of Zhejiang University School of Medicine; The Third Affiliated Hospital of Wenzhou Medical University; Lishui Municipal Central Hospital; Huzhou Central Hospital
• Investigators: Principal Investigator: Mao Zhang, MD, Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Estimated): June 6, 2026
• Primary Completion (Estimated): October 13, 2026
• Study Completion (Estimated): October 13, 2026

Study Registration Dates

• First Submitted: May 24, 2026
• First Submitted That Met QC Criteria: May 24, 2026
• First Posted (Actual): June 1, 2026

Study Record Updates

• Last Update Posted (Actual): June 1, 2026
• Last Update Submitted That Met QC Criteria: May 24, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Prognosis; Critically ill patients; Pupillary light reflex; Dynamic trajectory; Constriction Velocity
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Pathological Conditions, Signs and Symptoms; Critical Illness
• Other Study ID Numbers: 20260245

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared because the study involves sensitive clinical data from critically ill patients and data sharing is not currently covered by the informed consent or ethics approval. De-identified aggregate results will be reported in publications.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No